title: Direct activation of glomerular endothelial cells by anti-moesin activity of anti-myeloperoxidase antibody.
abstract: BACKGROUND
  Glomerular neutrophil infiltration has been thought to be a key pathological event in the development of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis involving glomerulonephritis. Accordingly, we sought to explore the molecules responsible for glomerular neutrophil accumulation.
  
  
  METHODS
  Glomerular neutrophil infiltration and renal chemokine expression in mice treated with anti-MPO IgG were evaluated. Chemokine expression in vitro induced by anti-MPO IgG was measured in the primary mouse glomerular endothelial cells (mGEC). The target molecule reacted with anti-MPO IgG on the mGEC was determined by peptide mass fingerprint analysis.
  
  
  RESULTS
  A significant glomerular neutrophil infiltration was observed in the mice administered with anti-MPO IgG. The expressions of CXC chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2), were significantly increased in the renal cortex, indicating that these chemokines contribute to the neutrophil infiltration. Based on the previous findings of upregulation of adhesion molecule expression in mGEC treated with anti-MPO IgG, we examined whether mGEC secrete these chemokines in response to anti-MPO IgG. Indeed, anti-MPO IgG induced secretion of KC and MIP-2, leading to neutrophil chemotaxis in vitro. Furthermore, complete depletion of MPO in mGEC and serum using MPO-deficient mice showed an upregulation of intercellular adhesion molecule-1, indicating cross-reactive molecule(s) were existing on mGEC. We identified the molecule as moesin by a proteomic approach.
  
  
  CONCLUSIONS
  The endothelial CXC chemokines, KC and MIP-2, contribute to infiltration of neutrophils in MPO-ANCA-associated vasculitis involving glomerulonephritis. The activation of glomerular endothelial cells by anti-MPO IgG appeared to directly involve a signaling through moesin.
authors.affiliation: Inflammation Program, Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nagao
authors.forename: Koya
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Utsunomiya
authors.forename: Mimiko
authors.initials: M
authors.lastname: Matsumura
authors.forename: Kan
authors.initials: K
authors.lastname: Saiga
authors.forename: Pi-Chao
authors.initials: PC
authors.lastname: Wang
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Minamitani
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Aratani
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood* / Q000276:immunology*; D015153:Blotting, Western; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000888:Antibodies, Anti-Idiotypic; D054426:Chemokine CXCL2; D018925:Chemokines; D008840:Microfilament Proteins; D012333:RNA, Messenger; C048844:anti-IgG; C071058:moesin; C074302:keratinocyte-derived chemokines; D009195:Peroxidase